Becoming bioavailable

Published: 1-Aug-2017

Working with a CDMO to engineer molecules for enhanced absorption

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Poorly soluble molecules in the pipeline can have a negative effect on your active pharmaceutical ingredient (API). From wasting the active or even having to double the API for the necessary patient absorption to take place, creating a formulation with a high solubility tolerance and the ability to reach the patient’s body is a crucial aspect of getting your drug to market faster.

To determine the type of solubility for each particle, the Biopharmaceutics Classification System (BCS) typifies a drug with its corresponding absorption rate. However, many belong to Class II, which translates to a formulation that exhibits poor solubility and high permeability. Poorly soluble drugs are less bioavailable and often need to be doctored during the formulation manufacturing process.

According to a Capsugel ebook, Perspectives on Overcoming Bioavailability Challenges, the company’s Head of Biotherapeutics, David Lyon, states: “Candidate molecules are increasingly complex, and target product profiles [are] increasingly specialised, leading to the need for enabling delivery technologies.”1 As such, for molecules to become more bioavailable, they often need to be modified. The process of increasing bioavailability, from the technology employed to the process and methods, is often dependent on outsourcing. This outsourcing will wind up with a contract development and manufacturing organisation (CDMO), although these organisations vary tremendously both in capability, size, structure, capacity and internal values.

Selecting an outsourcing partner

According to the 2017 Nice Insight Contract Development and Manufacturing Survey, outsourcing is a continuing element in both drug development and manufacturing.2 Outsourcing partners are selected in a variety of ways, with 36% of participants noting that they select them based on referrals. The Nice Insight annual research also indicated that the company’s perception in the community is important and a positive review can lead to a referral — and therefore more business for suppliers. This is reflected in the fact that 65% of respondents noted that references from colleagues or coworkers factor into the initial CDMO selection and are an important attribute when choosing a CDMO.

When respondents were prodded further regarding CDMO relationship structure and their ideal partnership scenario, the survey confirmed that suppliers are looking ahead to forging partnerships, as opposed to merely seeking a standardised approach to outsourcing on a project-by-project basis. This is evidenced by the preference for an ideal partnership. When asked what would most closely resemble the best alliance between the company and the outsourcing organisation, 32% described their ideal situation as one based on a tactical service provider, whereas 10% more (42%) indicated that they were seeking a preferred provider or strategic partner relationship with their outsourcing organisation. This attention to strategic partnerships is only building, as 46% confirmed they would be highly interested in this type of arrangement in the near future. This is equally promising for contractors that are seeking more control and a mutually beneficial agreement.

The need for a CDMO

The study also reinforces how necessary CDMOs are, especially in terms of formulation modification for bioavailability — the top reason for partnering with a CDMO was cited by respondents as access to specialised technologies. This was ranked higher than “partnering to improve quality,” which was voted the most important metric in 2016, as well as to “gain expertise” from both operations and from personnel.

Taking a molecule from concept to discovery and into a formulation has its own special set of challenges, in which bioavailability is definitely one of the most pressing, as this can affect the entire compound. Hence, CDMOs that can provide the technology needed and fulfil this niche in development will likely enjoy continued success.

Leading challenges lead the charge

Poor solubility leads to poor bioavailability, so the question becomes: how can molecules become more soluble? Because different compounds have significantly different chemical structures, the way different compounds act on them not only affects their absorption but will also depend on how they achieve solubility initially.

Again, in the Capsugel ebook, David Lyons commented on the differing types of bioavailability capacity. The way the particle undergoes this transformation is dependent on processes that change the chemical structure in differing ways. As Lyons remarked: “Look at a disease state such as hepatitis C. We’ve seen multiple molecules from numerous companies that tend to be very greasy and floppy, which seems to be a requirement for getting to the hep C binding site, and they all have very poor solubility.” This contrasts with kinase inhibitor oncology drugs, which he describes as “brick dust” molecules that are not soluble regardless of which solvent they are placed in.

Figuring out the formulation

Again, a key conclusion is that CDMOs that are equipped with the technology to turn formulations into bioavailable compounds will most likely be in demand within their network, leading to sustained business. Methods to increase the bioavailability of an API vary. While still in the preclinical phase, common forms of changing the particle structure needed for increased solubility include micronising or nanomilling. In lieu of this, it is common for salts and micronisation or particle size reduction to be employed to encourage dissolution.1

Alternative approaches to particle size reduction and the use of salts involve more complicated technology. Amorphous solid dispersion, which is done using spray drying or hot melt extrusion, is a more recent alternative method used to create a more dissolvable, readily bioavailable particle. Spray drying for pharmaceuticals is not a one size fits all solution, as is the case with other substances, such as in food or chemicals. Rather, it requires the use of many different types of machinery that are flexible and are employed depending on the API.

Available technology and CDMO capacity

There is not just one type of spray drying process, either, as aseptic gains traction against the common form of “traditional” spray drying. According to a Pharmaceutical Manufacturing article, “Spray Drying Enhances Solubility and Bioavailability,” aseptic spray drying is an alternative method that is especially useful in parenteral formulation.3 “Aseptic spray drying uses a hot gas to convert a liquid formulation into a dry powder that’s suitable for parenteral applications without the need for terminal sterilisation,” says Guy Tiene of Nice Insight. “The aseptic powder can then be filled into different presentations, such as vials. Currently, it is possible to aseptically spray dry products for up to 5 days continuously, manufacturing large, kilogram quantities of powder,” he explains. The other difference between these two processes are the conditions they are done in, with aseptic spray drying meeting the cGMP requirements for sterility.

An additional approach to creating increased bioavailability is through hot melt extrusion, or HME. With an HME approach, the API is mixed and heated along with a polymer; there is no solvent added. This mixture then cools and the melt with the most suitable properties is milled; the particles with the necessary properties are inserted into finished dosage forms, which include tablets, capsules, stick packs, etc.4

Another process for increasing solubility that houses a great deal of potential, especially for the most popular oral dosage form, is the self-emulsifying drug delivery system (SEDDS). SEDDS increases the bioavailability of these easy-to-take delivery forms and improves oral absorption via rapid self-emulsification. Self-emulsification is then followed by dispersion. This dispersion takes place at the absorption sites, which includes the GI track and will be released into GI fluids. According to “Self-Emulsifying Drug Delivery System: An Approach to Enhance Solubility,” published by the Pranveer Singh Institute of Technology, SEDDS are also ideal for increasing bioavailability.5

The micro/nanoemulsifed drug can easily be absorbed through lymphatic pathways, bypassing the hepatic first-pass effect. This is, in part, because of its “miniscule globule size.” SEDDs include a mixture of oils, surfactants and cosurfactants. This substance becomes emulsified in aqueous media under conditions that mimic those of the gastrointestinal (GI) tract to recreate digestion as well as the “gentle stirring” of the process.

This technology has heightened potential when dealing with drugs that are poorly soluble in nature and are intended for oral absorption. This is because, according to the paper, “following their oral administration, these systems rapidly disperse in GI fluids, yielding micro- or nanoemulsions containing the solubilised drug.”

This not only makes this procedure effective, but also contributes to the potential of increased promise, especially taking into consideration the scale-up processes involved as well as the tech transfer. Another area in which SEDDS have an increased potential to succeed has to do with the delivery form they affect — oral solid dosage.

Bioavailability can be particularly difficult in OSDs and contributes to the widespread industry concern of non-adherence or compliance problems. Whereas the more soluble the drug can become, the less is needed of the active particle ingredient — if a drug is highly soluble and will be absorbed greatly, then there is little need for so much of the API ingredient. A reduction in the amount of API that is used in the manufacturing process can lead to cost savings, while not compromising the efficacy of the drug product.

Increased bioavailability looks promising

Ultimately, the organisation looking to partner with a CDMO to engineer its molecules for increased absorption must employ the best technique to match customer needs. Factors to consider include time, cost, reliability, process development and method. These differing characteristics must be taken into account alongside (perhaps most importantly) technical capacity.

A measure of success does not end with capacity, although this does play a huge factor. Ultimately, the best method to get a molecule modified for bioavailability is dependent on a host of variables, including the type of API, the delivery method and other PK properties that need to be considered prior to selecting the perfect partner to bring the API from concept to formulation and finally into the commercial sphere.


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